As part of a comprehensive tuberculosis vaccine development effort over the past five years, we have identified more than 80 antigen genes from Mycobacterium tuberculosis (Mtb). From these genes, several vaccine candidates have been chosen on the basis of 1) their recognition by T cells form healthy PPD+ donors, and 2) preclinical studies in mice showing Th1 and CTL responses. Our current efforts, for which we seek matching funds, involve the optimization of vaccine constructs and delivery systems in animal models to maximize protective efficacy. Using the priority Mtb antigens we have identified we will produce poly-proteins with high expression levels in recombinant systems suitable for manufacture. We will use these protein antigens with state-of-the-art adjuvants, already tested in the clinic, along with delivery systems chosen to maximize T cell responses. We will focus on vaccine studies in the guinea pig and primate systems, as well as use mice to characterize immune responses induced by the experimental vaccines.